Identification of molecular mechanisms of cholestatic pruritus

• Applicant: Professor Andreas Emanuel Kremer, Ph.D.
• Subject Area: Gastroenterology ; Dermatology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260115148

Pruritus affects about 70% patients with cholestatic liver disease. In 5% of patients pruritus is seriously agonizing, uncontrollable with standard medical therapy and may even become a primary indication for liver transplantation. The molecular mechanisms of pruritus are unresolved and its treatment is an unmet medical need. Recently, we unravelled lysophosphatidic acid (LPA) as potential pruritogen in sera of cholestatic patients. Intradermal injection of LPA induced a dose-dependent scratching behaviour in mice. The LPA-forming enzyme autotaxin was increased in sera of patients suffering from pruritus and correlated with the itch intensity. The aims of this project are to i) identify the cellular source of the enzyme autotaxin, ii) to unravel the regulation of the autotaxin expression during cholestasis, iii) to analyse the histomorphological changes in the skin of patients suffering from pruritus and iv) to establish an animal model for cholestatic pruritus enabling to proof the causal relation between pruritus and increased levels of autotaxin and lysophosphatidic acid, respectively. Aim of this model will be the examination of novel therapeutic options to treat pruritus in cholestatic liver disease. The presented experiments and analyses will augment our understanding of cholestatic pruritus and offer novel therapeutic targets.

• DFG Programme: Research Grants
• International Connection: Netherlands, Switzerland, United Kingdom
• Participating Persons: Professor Dr. Ulrich Beuers; Professor Dr. Colin Henderson; Privatdozentin Dr. Anita Kremer; Professor Dr. Markus F. Neurath; Dr. Ronald Oude-Elferink; Professorin Dr. Kristina Schoonjans; Professor Dr. Michael Sticherling; Professorin Dr. Sonja Ständer; Privatdozent Dr. Stefan Wirtz